c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter

Background & Aims: Ileal bile acid malabsorption is present in Crohn’s ileitis. The molecular mechanisms of regulation of the apical sodium-dependent bile acid transporter (ASBT) by inflammatory cytokines in vitro and in vivo are investigated.Methods: Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs. Rat ASBT promoter transgenic, wild-type, and c-fos–null mice were treated with indomethacin to assess the response to acute inflammation of the ileal mucosa.Results: In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1β treatment, while c-fos and c-jun were up-regulated 2-fold. Human ASBT promoter activity was enhanced by c-jun and repressed by a dominant negative c-jun, c-fos, or a dominant negative c-fos. Meanwhile, c-fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-1β–mediated repression but led to a paradoxical increase in ASBT promoter activity. Indomethacin-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of ASBT was seen in c-fos–null mice. Indomethacin-induced ileal injury was greater in the c-fos–null mice compared with the wild-type littermates.Conclusions: Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter.